Phenthiazine derivatives



Patented June 30, 1959 PI-IENTHIAZINE DERIVATIVES Paul Gailliot, Paris, and Jacques Gaudechon, Thiais, France, assignors to Societe des Usines Chimiques Rhone-Poulenc No Drawing. Application July 13, 1956 Serial No. 597,582

Claims priority, application France July 18, 1955 3 Claims. (Cl. 260-443) 9 This invention is for improvements in or relating to phenthiazine derivatives.

A considerable amount of research and experimentation have heretofore been'conducted in the field of N- substituted phenthiazine derivatives and certain of these compounds have been found to possess valuable therapeutic properties. Some are useful primarily on account of their outstanding anti-histaminic activity, others because of their unusually powerful effect as potentiators of drugs which act upon the nervous system and of their efiicacy as anti-shock agents and yet others, for example, are effective agents for controlling or minimising motionsickness. It has nevertheless been demonstrated that of the very large number of possible N-substituted phenthiazine compounds that have been proposed or tested by various workers, only comparatively few have useful application in human or veterinary medicine and that both the nature and the degree of useful effect can radically alter with even apparently small changes in chemical structure.

It is the object of the invention to provide new therapeutically active phenthiazine derivatives.

The new compounds of the present invention are the racemic and optically active phenthiazine bases of the formula:

(in which Y represents an alkyl or alkoxy group containing not more than 4 carbon atoms, R represents a methyl or ethyl group and the grouping -N(R) represents either a dialkylamino group in which the alkyl groups contain not more than 4 carbon atoms or a heterocyclic group such as pyrrolidino, piperidino or morpholino), their addition salts formed with mineral or organic acids, their 8-halogeno-xanthines (in particular their 8-chloroand 8-bromo-theophyllinates), their theophylline-acetates and their quaternary ammonium derivatives. They have valuable pharmacodynamic properties by virtue of which they may be used in human and veterinary medicine. In particular, they have a remarkable eifect upon spasms, rigidities and contractures of divers origin. This effect can be demonstrated in the laboratory by the abolition of the chemical reflex of the spinal frog (Gautrelet, Technique Physiologique, p. 387 (1932)) or by the reduction of the algebraic summation of the extensor and tensor reflex or postural tonus in the rabbit (Gautrelet, 10c. 'cit., p. 315). In this respect a particularly active compound is 3-ethy'l-10-(3-dimethylaminobutyl)phenthiazine. The new compounds also have a very interesting inhibitory action on the hypophysis which may be demonstrated by, for example, the antagonistic action on the growth of the ovaries of the rat under the influence of the gonadotropic hormone (Burn, Biologische Auswertungsmethode, p. 137, (1937)). In this respect a particularly active compound is 3-methyl-10-(3-dimethylaminobutyl)phenthiazine. The compounds of the present invention also possess some utility as potentiators of anaesthetics and analgesics, as anti-shock agents, anti-emetics, sedatives, hypothermic agents, anti-inflammatory agents and antihistaminics.

For therapeutic purposes, the bases of general Formula I are preferably employed in the form of acid addition salts containing pharmaceutically acceptable anions (such as hydrochlorides and other hydrohalides, 8-chloroetheophyllinates, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, oxalates, methane sulphomates and ethane disulphonates) or of quaternary ammonium salts obtained by reaction with organic halides (e.g. methyl or ethyl iodide, chloride or bromide or allyl or benzyl chloride or bromide) or other reactive esters.

The aforesaid new phenthiazine derivatives may be prepared in a variety of different ways, of which the more important can be expressed generically as comprising the interaction of a phenthiazine compound containing a structure represented by the formula:

with a compound Q, the group P and the compound Q being such that Q will react with the compound of Formula II to introduce or form at the Ill-position of the ring a substituent grouping of the structure:

Rx III (wherein Y, R and the grouping -N(R) are as hereinbefore defined).

Specific embodiments of the generic process defined in the last preceding paragraph are as follows:

( 1) Interaction of a phenthiazine compound of the general formula:

with an aminohalogenoalkane of the formula:

z oH,oH,-cH-N(R),

or of the formula:

Z-CHCHZOHZN(R)2 (2) Condensationof an amine HN(R) with a phenthiazine of the type:

R VII (wherein X represents a residue of a reactive ester such as a halogen atom or a sulphonic or sulphuric ester residue).

Both processes (1) and (2) may be carried out with or without a solvent and optionally in the presence of an alkaline condensing agent such as an alkali metal or one of its derivatives (hydroxide, hydride, amide, alcoholate or organometallic derivative) and more especially sodium hydroxide or sodamide.

The following examples show how the invention may be put into practice. The melting points are those determined on the Kofler bench (K) or the Maquenne block (M).

Example I Sodamide (3.1 g.) is added to a boiling solution of 3- ethyl-phenthiazine (15 g.) in xylene (150 cc.) and l-dimethylamino-3-chlorobutane (10.7 g.) [prepared by analogy with Elderfield et coll., I. A. Chem. Soc. 68, 1521 (1946)], in xylene (15 cc.) is then run in over 30 minutes and the mixture is heated under reflux for 3 hours. After cooling, water (150 cc.) and hydrochloric acid (d:1.19, 14 cc.) are added and the aqueous layer is separated, washed with ether and treated with sodium hydroxide (d=1.33, 20 cc.). After extraction with ether (3 x 100 cc.), the combined ethereal extracts are dried over sodium sulphate and the solvent is evaporated. The residue (22 g.) is distilled in vacuo and 3- ethyl-l(3-dimethylaminobutyl) -phenthiazine 13.15 g.) B.P. 205-215 C./1 mm. Hg, is obtained. The hydrochloride of this base, obtained by the action of ethereal hydrogen chloride on the base in solution in acetone, melts at 135-1389 C. (K).

Example II Proceeding as in Example I but commencing with 3- methylphenthiazine (21.3 g.), xylene (210 cc.), sodamide (4.7 g.) and 1-dimethylarnino-3-chlorobutane (16.3 g.), there is obtained 3-methyl-10-(3-dimethylaminobutyl)- phenthiazine (22.5 g.), B.P. 190-200 C./0.7 mm. Hg. The action of ethereal hydrogen chloride on the base dissolved in acetone gives a hydrochloride, M.P. 198-200 C. (K).

Example III Proceeding as in Example I but commencing with 3- methylphenthiazine (21.3 g.), xylene (210 cc.), sodamide (4.7 g.) and 1-diethylamino-3-chlorobutane (19.6 g.) [prepared according to Elderfield et. coll. I. Am. Chem. Soc. 68, 1521 (1946)], there is obtained 3-methyl-10-(3- diethylaminobutyl)phenthiazine (24.1 g.), B.P. 195-205 C./0.6 mm. Hg, the hydrochloride of which melts at about 160 C. (K).

Example IV Proceeding as in Example I but commencing-with 3- methoxyphenthiazine (22.9 g.), xylene (230 cc.), sodamide (4.7 g.) and 1-diethylamino-3-chlorobutane (25.2 g.), there is obtained 3-methoxy-10-(3-diethylaminobutyl)phenthiazine (16.55 g.), B.P. 220-240 C./O.9 mm. Hg.

Example V Proceeding as in Example I but commencing with 3- ethylphcnthiazine (22.25 g.), xylene (220 cc.), sodamide (4.6 g.) and l-diethylamino-3-chlorobutane (19.4 g.),

there is obtained 3-ethyl-10-(3-diethylaminobutyl)phenthiazine (22.3 g.), B.P. 195-205" C./0.4 mm. Hg.

Example VI Sodamide (4.7 g.) is added to a boiling solution of 3- methoxyphenthiazine (22.9 g.) in xylene (230 cc.) and 1-pyrrolidino-3-chlorobutane (19.4 g.) [prepared by analogy with Elderfield et coil. 1. Am. Chem. Soc. 68, 1521, (1946)], B.P. 76-80" C./13 mm. Hg, dissolved in xylene (20 cc.) is run in over 50 minutes and the mixture is heated under reflux for 4 hours. After cooling, water (200 cc.) and hydrochloric acid (d=1.19, 19.5 cc.) are added and the aqueous layer is separated, washed with ether and then treated with sodium hydroxide (51:1.33, 16.5 cc.). After extraction with ether (3 x cc.), the combined ethereal solutions are dried over so dium sulphate and the solvent is evaporated.

The residue (35 g.) is distilled in vacuo and 3-methoxy- 10-(3-pyrrolidinobutyl)phenthiazine (21.4 g.), B.P. 230- 235 C./0.8 mm. Hg, is obtained.

Example VII 3-methyl-10-(3-chlorobutyl)phenthiazine (17.4 g.) is heated with dimethylamine (17.9 g.) in solution in ethanol (100 co.) in a stainless steel autoclave for 5 /2 hours at C. After cooling, the mixture is evaporated to dryness on the water-bath. Water (100 cc.) and sodium hydroxide (d=1.33, 10 cc.) are added to the residue and the base is extracted with ether (2 x 100 cc.). The combined ethereal solutions are extracted with N hydrochloric acid (2 x 50 cc.) and the hydrochloric acid solutions are washed with ether (50 cc.) and then treated with sodium hydroxide (d:1.33) until alkaline to phenolphthalein. They are then extracted with ether (2 x 50 cc.) and the combined ethereal solutions are dried over sodium sulphate. The solvent is evaporated and the residue (13 g.) is distilled in vacuo to give 3-methyl-10-(3-dimethylaminobutyl)phenthiazine (9.2 g.), B.P. -200 C./0.25 mm. Hg. The hydrochloride of this base, obtained by the action of ethereal hydrogen chloride on the base dissolved in acetone, melts at 198200 .C. (K).

3-methyl-10-(3-chlorobutyl) phenthiazine is obtained by the action of thionyl chloride in benzene in the presence of pyridine upon 3-methyl-10-(3-hydroxybutyl)phenthiazine, B.P. ZOO-206 C./0.5 mm. Hg, itself obtained by the action of 1-chloro-3-tetrahydropyranyloxybutane (B.P. 79-81 C./2 mm. Hg), on 3-methylphenthiazine in xylene in the presence of sodamide, the pyranyl derivative obtained being hydrolysed with dilute hydrochloric acid.

1-chloro-3-tetrahydropyranyloxybutane is prepared by the action of dihydropyran on l-chlorobutan-3-ol.

Example VIII Proceeding as in Example VII but commencing with 3-ethyl-10-(3-chlorobutyl)phenthiazine (18.2 g.) and dimethylamine (17.9 g.) dissolved in ethanol (100 cc.), there is obtained 3-ethyl-10-(3-dimethylamino'butyl)- phenthiazine (10.05 g.), B.P. 195-200 C./0.3 mm. Hg. The hydrochloride of this base, obtained by the action of ethereal hydrogen chloride on the base dissolved in ethyl acetate, melts at 138-141 C. (K) The iodomethylate, obtained by the action of methyl iodide on the base dissolved in acetone, melts at 169-170 C. (K).

3-ethyl-l0-(3-chlorobutyl)phenthiazine is prepared by analogy with 3-methyl-10-(3-chlorobutyl)phenthiazine (see Example VII).

Example IX Proceeding as in Example VII but commencing with 3-ethyl-10-(3-chloropentyl)phenthiazine (17 g.) and dimethylamine (17.9 g.) dissolved in ethanol (100 cc.), there is obtained 3-ethyl-10-(3-dimethylaminopentyl)- phenthiazine (6.03 g.), B.P. 195205 C./0.2 mm. Hg. The hydrochloride of this base, obtained by the action of ethereal hydrogen chloride on the base dissolved in ethyl acetate, melts at 128-130 C. (K).

3-ethyl-10-(3-chloropentyl)phenthiazine is obtained by the action of thionyl chloride in benzene in the presence of pyridine upon 3-ethyl-l0-(3-hydroxypentyl)phenthia- :zine, B.P. 215-225 C./0.3 mm. Hg, itself obtained by :the action of 1-chloro-3-tetrahydropyranyloxypentane, B.P. 86-88" C./ 2 mm. Hg, on 3-ethylphenthiazine in xylene in the presence of sodamide, the pyranyl derivative obtained being hydrolysed with dilute hydrochloric acid.

1-chloro-3-tetrahydropyranyloxypentane is prepared by the action of dihydropyran on 1-chloropentan-3-ol.

Example X 80% sodamide (8.5 g.) is added to a hot solution of 3-methylphenthiazine (32.2 g.) in anhydrous xylene (100 cc.) and the mixture is maintained at 100-110" C. for 1% hours. A xylene solution (81 cc.) containing 1-chloro-3-dimethylaminobutane (24.6 g.) is then run in over hour and the mixture is boiled for 1 hours. After cooling, it is treated with water (500 cc.) and hydrochloric acid (d=1.19, 25 cc.). The xylene is separated and the aqueous layer is extracted with ether (2 x 150 cc.). The xylene and the ethereal extracts are combined and treated with sodium hydroxide (d=1.33, 50 cc.). The mixture is extracted with ether (200 cc. followed by 100 cc.), the extracts are combined and dried over potassium carbonate and the ether is driven off on the water-bath. The residue (52 g.) is distilled an 3-methyl-10-(3-dimethylaminobutyl)phenthiazine (36.3 g.), B.P. 185-187" C./0.3 mm. Hg, is obtained. The hydrochloride of this base, prepared by the action of ethereal hydrogen chloride on the base dissolved in acetone, melts at 198-200 C. (K).

Example XI Proceeding as in Example X but commencing with QED- ' CH3 and their acid addition salts of which the added groups are therapeutically acceptable, wherein Y is selected from the class consisting of alkyl and alkoxy groups containing not more than 4 carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS 2,645,640 Charpentier July 14, 1953 FOREIGN PATENTS 47,552 India Dec. 16, 1952 OTHER REFERENCES Gilman et al.: J. Am. Soc., vol. 66 (1944), p. 891.

Viaud: J. Pharm. and PharmocoL, pp. 361 and 364.

vol. 6 1954 

2. AS A NEW COMPOSITION OF MATTER THE BASE 3-METHYL10-(3-DIMETHYLAMINOBUTYL)PHENTHIAZINE.
 3. A MEMBER OF THE CLASS CONSISTING OF THE RACEMIC AND OPTICALLY ACTIVE PHENTHIAZINE DERIVATIVES OF THE GENERAL PLANAR FORMULA: 